Journal
JOURNAL OF CLINICAL MEDICINE
Volume 10, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/jcm10132754
Keywords
iPSCs; neurons; PCDH19; neuronal progenitor cells; neurogenesis; disease modeling; neurological disease
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Funding
- Fondazione Bambino Gesu (Vite Coraggiose)
- Italian Ministry of Health
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PCDH19-related epilepsy is a rare genetic disease characterized by a heterogeneous phenotypic spectrum. Patients may exhibit intellectual disability, behavioral problems, and developmental delays. Seizures are often resistant to treatment, with an altered equilibrium in cell division being identified as a contributing mechanism to the pathogenesis.
PCDH19-related epilepsy is a rare genetic disease caused by defective function of PCDH19, a calcium-dependent cell-cell adhesion protein of the cadherin superfamily. This disorder is characterized by a heterogeneous phenotypic spectrum, with partial and generalized febrile convulsions that are gradually increasing in frequency. Developmental regression may occur during disease progression. Patients may present with intellectual disability (ID), behavioral problems, motor and language delay, and a low motor tone. In most cases, seizures are resistant to treatment, but their frequency decreases with age, and some patients may even become seizure-free. ID generally persists after seizure remission, making neurological abnormalities the main clinical issue in affected individuals. An effective treatment is lacking. In vitro studies using patient-derived induced pluripotent stem cells (iPSCs) reported accelerated neural differentiation as a major endophenotype associated with PCDH19 mutations. By using this in vitro model system, we show that accelerated in vitro neurogenesis is associated with a defect in the cell division plane at the neural progenitors stage. We also provide evidence that altered PCDH19 function affects proper mitotic spindle orientation. Our findings identify an altered equilibrium between symmetric versus asymmetric cell division as a previously unrecognized mechanism contributing to the pathogenesis of this rare epileptic encephalopathy.
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